Naturally occurring plant derived compounds are believed to afford some health benefits due in part to their antioxidant properties. These antioxidant activities may be important in preventing, treating or ameliorating many diseases, for example, cancer, neurodegenerative diseases such as Parkinson's and Alzheimer's, cardiovascular disease, and inflammation, as well as various conditions related to aging. Indeed, there is growing evidence that these compounds may be beneficial as chemopreventative, anti-inflammatory, immunomodulatory or cardioprotective agents. Accordingly, there is extensive research directed at identifying, extracting, purifying and developing plant derived antioxidant compositions for use as cosmetics, dietary supplements/nutraceuticals, food additives or pharmaceuticals.
Phenolic compounds, including their subcategory, flavonoids, are a group of compounds that possess antioxidant properties, which are present in all plants and have been studied extensively in cereals, legumes, nuts, olive oil, vegetables, fruits, tea and red wine. There is considerable interest in these naturally occurring antioxidants and in methods of extracting these compounds from various plants and plant products. For example, U.S. Pat. No. 6,620,452 describes a process for extracting plant phenolics from a fruit or vegetable, and steps to provide a liquid or solid concentrate thereof. U.S. Pat. No. 5,932,623 describes a process for obtaining extracts from unripe fruits and purports to identify the polyphenol products that are present in the extract and U.S. Pat. No. 5,994,413 describes a mixture containing polyphenol products extracted from unripe fruits.
Antioxidants, including phenolics, have been identified in, and extracted from, various berries. For example, U.S. Pat. No. 6,676,978 describes a method for isolating a mixture of anthocyanins, bioflavonoids and phenolics from an edible berry using adsorbent resins. The use of compositions comprising these compounds to provide antioxidant and anti-inflammatory activities to a mammal is also described. U.S. Pat. No. 6,312,745 describes a process for dehydrating berries while maintaining their antioxidant compounds/activities. U.S. Patent Application No. 2003/0031734 is directed to blueberry extracts with anti-oxidant and anti-cancer properties and their use to inhibit tumour cell growth and oxidative activity in an animal.
Many plant derived antioxidants have been proposed for use as dietary supplements. For example, U.S. Patent Application No. 2002/0068102 describes a dietary supplement comprising natural juices and its use to reduce cellular damage by scavenging free radicals within the human body. The natural juices can be derived from, for example, natural grape concentrate, a natural blueberry juice concentrate and/or other natural juice concentrates. U.S. Patent Application No. 2003/0008048 describes a dietary nutritional supplement that may comprise blueberry, for helping the body resist the effects of the ageing process and U.S. Patent Application No. 2003/003120 is directed to a phenolic fraction obtained from fruit and its use as a cosmetic, dietary, or nutraceutical preparation. Nutritional supplements are also described in U.S. Patent Application No. 2002168429. This patent application describes a method of producing reconstituted vegetable or fruit products that can then be used to prepare a dietary supplement. Fruit juices contemplated by this application include blueberry and cranberry juices, which are expressed from the berries and subsequently concentrated.
Fermentation can also be employed to modulate the antioxidant content of a plant derived products. For example, U.S. Pat. No. 5,498,412 describes a method for producing a natural antioxidant composition made from a plurality of fermented and milled materials of edible grains and pulses. In addition, wine fermentation has been reported to bring about multiple chemical modifications with respect to phenolic antioxidant profiles (Mazza, G., et al., (1999) J. Agric. Food Chem., 47, 4009-4017; Talcott, S. T. & J. H. Lee (2002) J. Agric. Food Chem., 50, 3186-3192).
Thus, the antioxidant content of fruits and vegetables varies considerably not only with species and growth conditions, but also with a number of other factors, including processing, fermentation, exposure to various temperatures, irradiation and pathogenic infection.
Diabetes, or diabetes mellitus, is a syndrome of disordered metabolism usually resulting from a combination of genetic and environmental factors that results in abnormally high blood sugar levels (hyperglycemia). Blood glucose levels are controlled by the hormone insulin, a product of the beta cells of the pancreas. Diabetes develops due to a diminished production of insulin (in Type 1) or resistance to the effects of insulin (in Type 2 and gestational). Both Type 1 and Type 2 diabetes lead to hyperglycemia. Hyperglycemia is a major contributor to the acute signs of diabetes, which include excessive urine production, resulting compensatory thirst and increased fluid intake. Serious long-term complications of diabetes include cardiovascular disease (doubled risk), and chronic renal failure, for example.
Type 2 diabetes mellitus is due to insulin resistance (or reduced insulin sensitivity), and reduced insulin secretion. The defective responsiveness of body tissues to insulin almost certainly involves the insulin receptor in cell membranes. In the early stage, the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood. Several factors may have a role in the development of Type 2 diabetes including central obesity (fat concentrated around the waist in relation to abdominal organs, but not subcutaneous fat) and environmental exposures, such as bisphenol A.
Type 2 diabetes frequently remains undiagnosed as visible symptoms are typically mild, non-existent or sporadic. Accordingly, severe long-term complications may result, including renal failure due to diabetic nephropathy, vascular disease (including coronary artery disease), vision damage due to diabetic retinopathy, loss of sensation or pain due to diabetic neuropathy, and liver damage from non-alcoholic steatohepatitis.
Type 2 diabetes usually is first treated by increasing physical activity, decreasing carbohydrate intake, and losing weight. It sometimes is possible to achieve long-term, satisfactory glucose control with these measures alone. However, the underlying tendency to insulin resistance is not lost, and so attention to diet, exercise, and weight loss must continue. The usual next step, if necessary, is treatment with oral antidiabetic drugs. Insulin production initially is only moderately impaired in type 2 diabetes. Oral medications may be used to improve insulin production, to regulate inappropriate release of glucose by the liver and attenuate insulin resistance to some extent (e.g., metformin), and to substantially attenuate insulin resistance. Oral medication eventually may fail due to further impairment of beta cell insulin secretion. At this point, insulin therapy is necessary to maintain normal or near normal glucose levels.
Obesity and diabetes have reached epidemic proportions throughout the world (James P T, Clin Dermatol 2004; 22: 276-280). Adipose tissue is now recognized as an endocrine organ that contributes to the physiopathology of type 2 diabetes. Adipokines, proteins produced by adipose tissue, have been identified as potential contributors to insulin resistance in humans (de Ferranti S, et al., Clin Chem 2008; 54: 945-955). Adiponectin is produced by differentiated adipocytes and circulates at high levels in the bloodstream (Kershaw E E, et al., J Clin Endocrinol Metab 2004; 89: 2548-2556). Low levels of circulating adiponectin are associated with insulin resistance and the presence of metabolic syndrome (Mojiminiyi O A et al., Int J Obes (Lond) 2007; 31: 213-220; and Hivert M F, et al., J Clin Endocrinol Metab 2008; 93: 3165-3172). Increasing adiponectin expression may be integral to the therapeutic effect of antidiabetic medications such as PPARγ agonists (Thiazolidinediones) (Yang B. et al., BMC Pharmacol 2004; 4: 23; and Katsuda Y, et al. J Atheroscler Thromb 2007; 14: 19-26) or CB1 blocker (Rimonabant) (Van Gaal L F, et al., Eur Heart J 2008; 29: 1761-1771; and Scheen A J, et al. Eur Heart J 2007; 28: 1401-1402; author reply 1402). The best-characterized molecular mechanism mediating the metabolic and vascular actions of adiponectin involves stimulation of AMP kinase (AMPK) activity (Guerre-Millo M. Diabetes Metab 2008; 34: 12-18).
Members of the genus Vaccinium have been used traditionally for the treatment of diabetic symptoms and are hence reputed to be antidiabetic (Chambers B K, et al. Diabetes Care 2003; 26: 2695-2696; Jellin J, et al., Medicines Comprehensive Database. ed. Pharmacist's Letter/Prescriber's Letter. pp. 2239. Stockon, C A: Therapeutic Research Faculty. 2005; Haddad P S, et al., J. Herbs, Spices Med Plants 2003; 10: 25-45, and United States Patent Publication No. 2009/0176718). Extracts of various parts of the V. angustifolium plant were shown to possess insulin- and glitazone-like properties while also protecting cells against glucose toxicity (Martineau L C, et al., Phytomedicine 2006; 13: 612-623). The blueberry fruit is rich in phenolic compounds such as hydroxycinnamic acids, flavonoids and proanthocyanidines (Kahkonen M P, et al., J Agric Food Chem 2001; 49: 4076-4082; Yi W, et al., Food Res Int 2006; 39: 628-638; Matchett M D, et al., J Nutr Biochem 2006; 17: 117-125).
More recently, it has been shown that fermentation (or “biotransformation”) of blueberry juice with a novel strain of bacteria isolated from the blueberry flora and named Serratia vaccinii, increases its phenolic content and antioxidant activity (Martin L, et al., J Sci Food Agri 2005; 85: 1477-1484) and modifies its biological activity (Vuong T, et al., Can J Physiol Pharmacol 2007; 85: 956-965). In vitro, this biotransformed juice has been shown to increase AMP-activated protein kinase phosphorylation and glucose uptake in muscle cells and adipocytes, but inhibited adipogenesis (Vuong T, et al., supra).
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.